Humanized mouse model supports development, function, and tissue residency of human natural killer cells

Significance Humanized mice represent a promising approach to study the human immune system in health and disease. However, insufficient development and function of human lymphocytes limit the applicability of humanized mice for cancer biology and therapy. We demonstrate that human SIRPA and IL15 knock-in (SRG-15) mice support efficient development of circulating and tissue-resident natural killer (NK) cells, intraepithelial lymphocytes, and innate lymphoid cell subsets. In contrast to previous humanized mouse models, human NK cells in SRG-15 mice mediate efficient antibody-dependent cellular cytotoxicity and thereby enable NK cell-targeted cancer immunotherapy of tumor xenografts. As such, SRG-15 humanized mice may facilitate translational research by enabling the development of novel NK and CD8+ T cell-based therapeutic approaches that target human infections and malignancies. Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2−/− Il2rg−/− background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg−/− (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt’s lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.